We have just completed a Phase I dose/toxicity trial for children and young adults with recurrent solid tumors using 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) to target the somatostatin receptor type 2 (sst2) expressed on tumor cells. Potential subjects were screened for tumor expression of sst2 using 111In-DTPA-Octreotide (Octreoscan) as a surrogate for 90Y-DOTATOC. No dose limiting toxicities were observed;furthermore, we observed an excellent response rate with 30% partial responses, 24% minimal responses, and 24% stable disease in children with brain tumors, neuroblastoma, and neuroendocrine tumors who had failed previous first and second line therapeutic options. Results of this trial were presented at the 2008 American Society for Clinical Oncology meeting along with other Phase I trials in children. Our trial of molecularly targeted peptide radiotherapy using 90Y-DOTATOC was the only one of the pediatric Phase I trials that demonstrated any complete, partial, or minimal responses. These encouraging Phase I results have prompted us to design this Phase II efficacy trial to test our hypothesis that 90Y-DOTATOC is an effective therapeutic agent in children and young adults with neuroblastoma and neuroendocrine tumors that express sst2 as determined by Octreoscan. We will also test the hypothesis that 13-cis retinoic acid (cisRA) can potentiate the efficacy of 90Y-DOTATOC in recurrent or refractory solid tumors that express sst2. Exciting new results in our laboratory demonstrate that cisRA increases expression of sst2 in both neuroblastoma and neuroendocrine tumor cells. These promising observations provide a rationale for design of the Phase II trial as a randomized comparison of 90Y-DOTATOC with or without cisRA in children and young adults with neuroblastoma or neuroendocrine tumors. The Phase I trial was based on fixed dosing of 90Y-DOTATOC, limiting the radiation dose to kidneys to <21Gy. An important caveat is that this renal radiation dose was chosen using external beam radiation limits for 90Y- DOTATOC, a radiopharmaceutical that is administered IV to deliver internal radiation directly and selectively to the tumor cells. In this Phase II trial, we also plan to test the hypothesis that individualized dosimetry will provide more accurate estimates of renal radiation dosing and enable us to increase the dose to tumor while still limiting the renal dose in each subject to a safe level of 23 Gy. Taking into account the promising results of the Phase I trial, namely, an excellent response rate with no dose limiting toxicities;our new data demonstrating cisRA mediated upregulation of sst2;and new, individualized renal dosimetry data from five subjects in the Phase I trial, we propose to conduct a randomized Phase II trial of 90Y-DOTA-tyr3-Octreotide with or without 13-cis retinoic acid in children and young adults with sst2 positive neuroblastoma or neuroendocrine tumors. We will employ individualized dosimetry to deliver the maximum allowable radiation dose to tumor while limiting renal radiation dose to 23Gy. PUBLIC HEALTH RELEVANCE: Children and young adults with recurrent neuroblastoma and neuroendocrine tumors will be given targeted radiotherapy with a radioactive somatostatin look-alike drug (Octreotide) that seeks out tumor cells which express the somatostatin receptor. Half of the patients will also receive retinoic acid to see if this improves the effectiveness of the radiolabeled Octreotide. A nuclear medicine test will be performed to determine how much radioactive Octreotide can be given safely without toxicity to the kidneys.